Statins have, at present, the potential to provide a new therapeutic target for various neurological diseases. It is well established that statins reduce cholesterol levels and prevent coronary heart disease. Moreover, evidence suggest that statins have additional properties such as endothelial protection via action on the nitric oxide synthase system as well as antioxidant, anti-inflammatory and anti-platelet effects. These properties might have potential therapeutic implication not only in stroke, but also in neurological disorders such as Alzheimer disease, Parkinson's disease, multiple sclerosis and primary brain tumors. In addition to their potent anti-atherosclerotic and cardio-protective effects, compelling clinical and preclinical studies delineate the neuro-protective efficacy of statins in all these neurological disorders. It is apparent from these studies that most patients with central nervous system disorders probably benefit to some extent from lipid-lowering therapy. But data are not univocal, and we must also consider the adverse effects due to the administration of lipid-lowering therapy.Thus, in these scenarios the effectiveness of statins in treating stroke, Alzheimer's disease, Parkinson disease, multiple sclerosis, and primary brain tumors have to be conclusively proven in vivo and/or in adequate clinical trials.

So we have had trials and the data don't tell us enough about dose and efficacy and we need more trialsSo the question we have been asking is who are going to fund these trials? and even if they are funded then what? What is the pathway to prescription?. I think too little thought is given to this critical question, because without the right answer the studies will falter and go nowhere. This is the question that the ethical committees need to ask and not accept some stock-answerDo academics believe that the regulatory system, they helped create to give pharma a toughtime, will bend for them...Do we need to talk to pharma to see if they have a new statin on the shelf that they can take into phase III, because this is perhaps part of the benefit of these trials as it shows pharma what to do and what not to do in their trials and it identifies targets. Will they go down the HMG-CoA pathway to get new drugs. Maybe they are doing this already and we don't know

Whilst this post may seem directed at Sir Jeremy and related neuros that gave use the statin conundrum, it is not. It is a problem for others (academic neuros) including ProfG who are doing studies with other repurposed drugs.

MS SMART is starting with Amiloride (Patent filed with MRC-WO2008007131...so MRC hopefully have been paying since 2006 to keep that alive); Ibudilast there is company behind this one Medicinova...so interesting that there are two academic led trials going on? The original Japanese patent was from 1998 and, riluzole (There is a patent filed in 1998, but I suspect company interest in this has expired...When ProfG and I tried to get this trialled in progressive MS in about 2001/2002 a certain company (or should I say the accountants of a certain company) weren't interested...I think this was too early for the approach. If we had gone back 5-10 years later the penny may have dropped. Sometimes you can be too far ahead of the curve. Now it may be too late for the approach.The purpose of this post is to say that we have to think what's next. There is not point in starting without this thought.This requires planning and maybe action, certainly by the medical fraternity, funders of studies but also people power. Maybe if we can make progressive MS an orphan disease by the time trials are finished you would only need one phase III trial and so lower the hurdle that academic groups face to get drugs to pwMS. This would also help pharma too.

OBJECTIVE: To examine the temporal evolution of spinal cord (SC) atrophy in multiple sclerosis (MS), and its association with clinical progression in a large MS cohort.METHODS: A total of 352 patients from two centres with MS (relapsing remitting MS (RRMS): 256, secondary progressive MS (SPMS): 73, primary progressive MS (PPMS): 23) were included. Clinical and MRI parameters were obtained at baseline, after 12 months and 24 months of follow-up. In addition to conventional brain and SC MRI parameters, the annualised percentage brain volume change and the annualised percentage upper cervical cord cross-sectional area change (aUCCA) were quantified. Main outcome measure was disease progression, defined by expanded disability status scale increase after 24 months.RESULTS: UCCA was lower in SPMS and PPMS compared with RRMS for all time points. aUCCA over 24 months was highest in patients with SPMS (-2.2% per year) and was significantly higher in patients with disease progression (-2.3% per year) than in stable patients (-1.2% per year; p=0.003), while annualised percentage brain volume change did not differ between subtypes (RRMS: -0.42% per year; SPMS -0.6% per year; PPMS: -0.46% per year) nor between progressive and stable patients (p=0.055). Baseline UCCA and aUCCA over 24 months were found to be relevant contributors of expanded disability status scale at month-24, while baseline UCCA as well as number of SC segments involved by lesions at baseline but not aUCCA were relevant contributors of disease progression.

If you have progressive disease you are loosing spinal nerves at a faster rate than if you are not-progressing and this is more evident in SPMSers and PPMSers than RRMSers. So this suggest that you can see differences at 2 years. There was a big difference in the spinal cord volume but the effect was much smaller when studying brain volume.so one wonders why brain volume is a core for trials of progressive MS are neuros making harder for themselves to find a treatment?

How do you feel about your neurologists engaging with you using social media? #MSBlog #MSResearch"I was meant to attend the 'Multiple Sclerosis Management 2014: Raising expectations' meeting in Vienna yesterday, but had to pull out because of domestic commitments. I managed to give my talk using a webinar format at it seemed to go well, but it is difficult to know how well when you have no real eye contact with the audience. I was asked to talk on the role of social media in communicating and raising MSer expectations. This is now the fourth time that either Prof B or myself have been asked to do this. It must relate to us being bloggers. I think the community are beginning to see that the advantages of being involved in social media outweigh the disadvantages. I also hope by giving these talks more clinicians and scientists will become engaged either by starting their own blogs or by simply using this platform and doing guest posts.""As a result of a surge in interest in social media and the ease of use of setting-up and running webinars using Google Hangouts we will be running a series of these after the summer. To get a sense of adoption of social media by the MSology community can you please complete this short survey. Thanks. "

Background: Nabiximols (Sativex®), in a cannabinoid-based oromucosal spray, is an add-on therapy option for patients with moderate to severemultiple sclerosis spasticity (MSS) resistant to other medications. The study objective was to provide long-term data on clinical outcomes, tolerability, quality of life and treatment satisfaction for MSS patients receiving nabiximols in routine care. Methods: This was the 12-month prolongation of the MOVE 2 study, an observational, prospective, multi-centre 3-month non-interventional study conducted in a routine care setting across Germany. Structured documentation forms, questionnaires and validated instruments were used for data collection. Results: In total, 52 patients were included in the effectiveness analysis after 12 months. The mean spasticity numerical rating scale (NRS, 0-10) score decreased significantly from 6.0 ± 1.8 points at MOVE 2 baseline to 4.8 ± 1.9 points after 1 month and remained on this level after 12 months (4.5 ± 2.0 points); in patients classified as 'initial responders' (≥20% NRS improvement after 1 month) similar results were found (baseline: 6.3 ± 1.4 points; after 1 month: 4.0 ± 1.0 points; after 12 months: 4.3 ± 1.9 points). The majority of patients (84%) did not report adverse events.

Conclusion: Real-life data confirm the long-term effectiveness and tolerability of nabiximols for the treatment of resistant MSS in everyday clinical practice.

Yet more evidence for some effect of Sativex in the people hat respond to the drug. There were 16% reporting adverse events. The central problem for the UK is not the benefit that needs to be shown but that the drug is cost effectiveness, otherwise it will always have problems in UK PLC.

Furthermore maybe this cost will be the problem in North America...because of cheaper "unregulated" competition

There are numerous Hemp growing operations springing up especially in Canada and Colorado where the possession/growing is becoming accepted.

Unlike pharma cartels, there is market competition apparently going on and the cost of medicinal pot is tumbling.

Add to this the lack of requirement to demonstrate real efficacy for medicinal purposes,like other nutricienticals, then real pharma is going to have their work cut out to get their foot in to the medicinal cannabis market.

The number of pot growers stating that they know it works because they use it themselves (say no more) and the effects are always remarkable....Much of it sounds however frankly unbelievable. There are millions of people using cannabis and if cannabis could really reverse (I am not saying their is no benefit..but cures?) disease conditions...the proof would be there or easy to come by. They sound like (bad) used car salesmen, who would sell their gran for a quick buck.

The failures of academic neuros to show benefits from THC in progression (CUPID) may have probably killed off interest in research in this area room a pharmaceutical perspective.

However because of the wide availability and use of marijuana, outside of pharma, suggests that it would be worth further investigating the effects on progression, where the majority of research suggests a neuroprotective potential.

It is clear that some components of cannabis can compete to stop this benefit being realised. Would you want to know which mix of components offer benefit...This needs real data not the hear say from pot shops.

What is the merit say of a 1:1 mix of Cannabidiol over tetrahydrocannabinol say compared to 20:1 or no cannadidiol. It is claimed that CBD reduces the side effects of THC...so why therefore would it not reduce the therapeutic effects? Where's the data, where's the biology.

OBJECTIVES:Summarize the data on sexual disorders in women with multiple sclerosis (MS).METHOD:Review of 99 Pubmed articles covering sexual dysfunction in women with MS.RESULTS:Prevalence of dysfunction in women with MS varies from 34% to 85%. They include poor vaginal lubrication, poor clitoral erection, and anorgasmia, which correlate with level of disability. Specific brain stem and pyramidal lesions appear to correlate with anorgasmia. Age and duration of the disease correlate with sexual disorders, but not age at onset. Secondary consequences of MS, including bladder and bowel dysfunction, spasticity, pain, fatigue, depression, anxiety, and side effects of medication contribute to sexual dysfunction. Treatments can involve alpha-blockers or phosphodiesterase-5 inhibitors to increase smooth muscle relaxation, while lubricants and oestrogen therapy can help vaginal dryness, burning and dyspareunia. Antidepressants can delay (or abolish) orgasm, suggesting reducing dosage or combining them with PDE5 inhibitors. Counselling should emphasize planning sexual activities, reducing fatigue, managing positions, preventing incontinence, promoting sexual aids, extra-genital and other sexual options to achieve pleasurable and intimacy. Psychosocial interventions should include couples' relationship and communication skills to increase satisfaction.CONCLUSION: Sexual dysfunctions in women with MS are amenable to treatments covering primary, secondary and tertiary consequences of the disease.

BACKGROUND: The chronic cerebrospinal venous insufficiency theory proposes that altered cerebral venous hemodynamics play a role in the pathophysiology of multiple sclerosis. We aimed to explore the validity of this hypothesis by assessing the diagnostic criteria for chronic cerebrospinal venous insufficiency in persons with and without multiple sclerosis. METHODS: We compared the proportion of venous outflow abnormalities between patients with multiple sclerosis and healthy controls using extracranial Doppler ultrasonography and gadolinium-enhanced magnetic resonance venography. Interpreting radiologists were blinded to the clinical status of participants.RESULTS: We enrolled 120 patients with multiple sclerosis and 60 healthy controls. High proportions of both patients (67/115 [58%]) and controls (38/60 [63%]) met 1 or more of the proposed ultrasound criteria for diagnosis of chronic cerebrospinal venous insufficiency (p = 0.6). A minority of patients (23/115 [20%]) and controls (6/60 [10%]) fulfilled 2 or more of the proposed criteria (p = 0.1). There were no differences between patients and controls in the prevalence of each individual ultrasound criterion. Similarly, there were no differences in intracranial or extracranial venous patency between groups, as measured by magnetic resonance venography.INTERPRETATION: We detected no differences in the proportion of venous outflow abnormalities between patients with multiple sclerosis and healthy controls. Moreover, our study revealed significant methodologic concerns regarding the proposed diagnostic criteria for chronic cerebrospinal venous insufficiency that challenge their validity.

So there we have it the The Bard Zamboni's research was not reproducible...but we knew that quite a few years ago.Here are the latest Google Trends:

Friday, 27 June 2014

How do we define secondary progressive MS? Is it a rational therapeutic target? #MSBlog #MSResearch"An interesting debate has started within the UK MSology community. Do DMTs that have been shown to reduce relapses, relapse associated disability progression, MRI inflammatory activity (focal lesions), MRI associated damage (T1 blackholes and brain volume loss) delay the onset of SPMS? Some of us want class-1 randomised controlled, double-blind, data to show this before we accept that DMTs may delay the onset of SPMS.""I think this argument is superfluous, SPMS is a academic construct to explain a clinical phenotype and is not backed by biology. Most of us accept that the pathological substrates that underpin progressive MS are demyelination, neuroaxonal loss and gliosis, which when combined with a failure of neuronal reserve manifests as progressive MS clinically. If we accept a biological definition of progression then progressive MS is present from the start of the disease, in fact it probably starts before you present with your first clinical attack or symptoms. New data shows that RISers (people with radiologically-isolated or asymptomatic MS) already have brain atrophy. In my opinion, any treatment that reduces or prevents these pathological mechanisms that drive progression will delay the onset of clinically-defined SPMS.""The problem with our clinical definitions is that they are so unreliable and are a moving target. In the pre-DMT era SPMS used to be diagnosed when MSers had EDSS scores of 2.0-2.5. Now that we have DMTs most people will only diagnose SPMS when MSers are more disabled with EDSS scores above 4.0. Why? Simply because funders will only pay for DMTs in MSers who have relapsing disease. As soon you label someone with SPMS it makes it difficult to prescribe DMTs. How can we rely on a clinical definition of SPMS, when we are continuously changing the definition?""I have sat on countless steering committees that have tried to operationalise time to onset of SPMS as a clinical outcome. It has not been possible to reach any consensus. Most of us are now trying to use EDSS milestones instead, for example time to confirmed disability progression to EDSS 4.0. Why 4.0? Most natural history studies suggest that once MSers hit 4.0 the disease progresses relentlessly regardless of whether or not they have superimposed relapses or not. I am not sure if this is correct. Most of our observations are based on natural history studies and not what happens on DMTs. A lot of new emerging data suggests that things are very different in the DMT era; we cannot rely on natural history data to make decisions about the onset of SPMS. For one we need to consider the concept of the therapeutic lag; this based on the hypothesis that in MSers with reduced reserve capacity, disease progression occurring now has been primed by inflammation from one to two years ago. If you switch off inflammation now you need to wait three to five years to see an impact."

"The other problem I have is that our definition of SPMS tends to be defined by lower limb motor activity. What about the other neurological systems? This is why I think we need to seriously rethink our definition of what is progressive MS."

There is little doubt in my mind that if DMTs reduce end-organ damage they will delay disability progression and delay the clinical onset of SPMS, however, you want to define it. At a recent Charcot meeting there was a very eloquent presentation by Maria Trojano, who reviewed all the real-life data sets on the impact of DMTs and the course of MS; apart from the British Columbia register all the other data sets showed that DMTs delayed the onset of clinically-defined SPMS. The issue for purists is that this data is not collected in randomised trials and is therefore unacceptable. What do they want?"

"This debate reminds me of what happened in the rheumatology field 15 years ago. When I did my PhD I worked in Marc Feldmann's and Tini Maini's laboratory; this duo pioneered the clincal development of anti-TNF (tumour necrosis factor alpha) therapy in rheumatoid arthritis. Anti-TNF therapy switched off the inflammation and made RAers feel well. This triggered a debate whether or not this would prevent end-organ joint damage and the need for joint replacement therapy in the future. Marc Feldmann had no doubt about the longterm impact of these therapies. Why? He understood the biology of RA and knew that inflammation was the driver of end-organ damage; switch it off and you protect joints. Marc has now been proved correct; it is clear that the number of joint replacements required in RAers has plummeted. Maybe we should start counting walking sticks and wheelchair numbers? We already do; EDSS 6.0 and 7.0 are measured surrogates for sticks and chairs. If DMTs are reducing time to EDSS 6.0 and 7.0 they are reducing the needs for sticks and chairs. If the clinical onset of SPMS is linked to EDSS progression then DMTs are delaying the onset of SPMS."

"Unfortunately, unlike joint replacement therapies in RA, or renal dialysis, or transplantation in other end-stage organ failures, we can't replace the brain and spinal cord, nor can we restore their function when they fail. It is time to think of DMTs as preventive therapies; prevention of disability. We shouldn't get too bogged down in how we define this; particularly clinically. We need to remember the iceberg analogy."

OBJECTIVE:Single nucleotide polymorphisms (SNPs) in the genes encoding interferon response factor (IRF)-5, IRF-8 and glypican-5 (GPC5) have been associated with disease activity in multiple sclerosis (MS) patients treated with interferon (IFN)-β. We analysed whether SNPs in the IRF5, IRF8 and GPC5 genes are associated with clinical disease activity in MS patients beginning de novo treatment with IFN-β.METHODS:The SNPs rs2004640, rs3807306 and rs4728142 in IRF5, rs13333054 and rs17445836 in IRF8 and rs10492503 in GPC5 were genotyped in 575 patients with relapsing-remitting MS followed prospectively after the initiation of their first treatment with IFN-β.RESULTS:62% of patients experienced relapses during the first 2 years of treatment, and 32% had disability progression during the first 5 years of treatment. Patients with a pretreatment annualized relapse rate >1 had an increased risk of relapse (hazard ratio 1.53, 95% confidence interval 1.24-1.90) and progression (hazard ratio 1.48, 95% confidence interval 1.10-1.99) on treatment and patients with breakthrough relapses in the form of relapses during the first 2 years of treatment had an increased risk of progression during the first 5 years of treatment (hazard ratio 2.04, 95% confidence interval 1.47-2.85).The gene variants in IRF5, IRF8 and GPC5 were not associated with risk of relapse or disease progression.CONCLUSIONS:Pretreatment relapse rate and clinical disease activity during the first 2 years of treatment may be associated with disease progression in MS patients treated with IFN-β. Genetic analysis of the studied gene variants do not provide additional information.

Predict who will respond and who will not respond to drugs is of interest to neuros treating you, but less of a concern to pharma who just want to sell to every one...which is rather disturbing that they are happy for you to pay for something that may be effectively useless. If you look in genes you maybe be able to work out who responds and who doesn't. This is called pharmacogenomics. Whilst this study they did not really find anything of interest in this respect it does show that 2% of patients experienced relapses during the first 2 years of treatment, and 32% had disability progression during the first 5 years of treatment and relapse history predicts relapse. This is hardly NEDA, is this what you want?

Thursday, 26 June 2014

"The study below using data from the Scottish Primary Care dataset shows that MSers are much more likely to have one or more comorbidities, or other diseases. The problem with this study is that it implies these other disease are independent of MS, when they are clearly not and a large number of them are manifestations of MS. For example, the list of mental health conditions includes depression, anxiety, stress related & somatoform disorders, drugs misuse, anorexia or bulimia, bipolar disorder and schizophrenia. All these disorders could be a manifestation of MS. What is interesting is that MSers are less likely to be diagnosed with coronary heart disease or hypertension. The latter comes as a surprise to me; I was under the impression that MSers were at higher risk of coronary heart disease, mainly due to the common association with smoking and obesity, both of which are commoner in MSers that the general population. I will need to check to see if this finding can be reproduced in other datasets. What this study does show is that MS is a very complex disease and has numerous associated comorbidities that all need addressing. This has resource indications and needs to be taken into account with any healthcare service development. Do you have a problem with associated diseases? Does your doctor treats them as part of your MS or does he/she treat them as being unrelated to MS?"

Retrospective studies show that natalizumab modifies oligoclonal immunoglobulin (IgG) bands (OCBs) in the cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients. In this study, we prospectively analyzed both serum and CSF samples from 24 MS patients, before and after 2 years of natalizumab-based therapy. Our results showed complete (55%) or partial (27%) disappearance of the OCBs in CSF samples that were taken after 2 years of therapy. Intrathecal IgG production, represented by the IgG index and IgGLoc, was also quantitatively reduced. Our data showed that natalizumab substantially modulates both intrathecal polyclonal and oligoclonal IgG production: This effect was much more potent than was previously reported

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Oligoclonal bands are products of a restricted set of antibody producing cells which are often found int he brain of MSers. This is an indication of immune activation in the brain. Can it be stopped. In the past people have looked at the spinal fluid of people on tysabri and found a difference in this study they took a spinal tap before starting tysabri and looked again 2 years later and this study suggests that they disappear in 55% of people and indicates that blocking cells from entering the brain quells the immune system

Wednesday, 25 June 2014

Are you planning to have extend your family? Learn about MS and pregnancy. #MSBlog #MSResearch

"Wow, wait a moment. The paper below makes the following conclusion 'pregnancy might in fact accelerate the rate of transition to SPMS'. This is based on the a relative risk of 1.25, in other words females who have been pregnant are 25% more likely to transition to SPMS than those who have not been pregnant. The devil however is in the detail; the 95% confidence intervals are from 0.39 to 3.96. This mean that there is a 95% chance that the real answer is between these two boundaries. In other words pregnancy may actually reduce your risk of becoming secondary progressive by 61% or it may increase your risk by up to 400%. The fact that the confidence interval straddles 1.0 tells you that this result is not significant and hence pregnancy does not increase your risk of becoming secondary progressive. In the same data set pregnancy reduces your chances of irreversible disability by 84% (0.16 (0.03; 0.79)); please note this result is significant because the so called 95% confidence intervals don't cross 1.0."

"Could there really be a disconnect between a positive impact on relapses, the acquisition of irreversible disability and the onset of SPMS? I suspect not as several other data sets suggest that pregnancy (single or multiple) has a positive impact on the progressive phase of the disease."

"It is interesting to see how much activity is happening in relation to pregnancy and MS. Why? I suspect this is being driven by Pharma who think this will be one of the main differentiators in the DMT market. In particular, the oral DMT market. I have a sense of a deja vu; this is what happened with NABs in the interferon wars. I predict we will see a spate of conferences and satellite symposia dedicated to the topic or pregnancy in MS. Despite being cynical, pregnancy is an important issue and if your are planning to start, or extend, your family you need to be aware of all the relevant issues concerned. For more information please read other posts on this site about pregnancy. You can use the Google search app on the left hand side of the bog; please note this app is only accessible on the web version of the blog."

PURPOSE: The purpose was to examine the impact of pregnancy on the rates of relapses, progression to irreversible disability, and transition to secondary progressive multiple sclerosis (SPMS) in MSers with RRMS.

METHODS: We retrospectively followed two subcohorts of women with RRMS: pregnant (n = 254) and non-pregnant (n = 423). We obtained data on demographic, lifestyle, and clinical characteristics from patient records.

CONCLUSIONS: Pregnancy likely ameliorates the short-term course of RRMS in terms of the rates of relapses and progression to irreversible disability. Over the long term, it appears to have no material impact on these outcomes, and might in fact accelerate the rate of transition to SPMS.

BACKGROUND:Falls are common in people with multiple sclerosis (PwMS). Previous studies have generally included small samples and had varied methods.OBJECTIVES:The objectives of this paper are to compile fall rates across a broad range of ages and disease severity and to definitively assess the extent to which MS-associated and demographic factors influence fall rates.METHODS:Individual data from studies in four countries that prospectively measured falls for three months were analyzed. We determined fall rates, prevalence of fallers (≥1 falls) and frequent fallers (≥2 falls), location and timing of falls, and fall-related demographic factors.RESULTS: A total of 537 participants reported 1721 falls: 56% were fallers and 37% frequent fallers. Most falls occurred indoors (65%) between 6 a.m. and 6 p.m. (75%). Primary progressive MS was associated with significantly increased odds of being a faller (odds ratio (OR) 2.02; CI 1.08-3.78). Fall risk peaked at EDSS levels of 4.0 and 6.0 with significant ORs between 5.30 (2.23-12.64) and 5.10 (2.08-12.47). The fall rate was lower in women than men (relative risk (RR) 0.80; CI 0.67-0.94) and decreased with increasing age (RR 0.97 for each year, CI 0.95-0.98).CONCLUSION: PwMS are at high risk of falls and there are important associations between falls and MS-associated disability, gender and age.

Falling is common in MSers to it is vital that you maintain good bone health.

Treatment paradigms in multiple sclerosis: who, when and how to treat? Willis MD, Robertson NP. J Neurol. 2014 Jun. [Epub ahead of print]With an increasing array of disease-modifying therapies (DMTs) for multiple sclerosis (MS) now available, clinicians are faced with a range of difficult treatment decisions relating to patient selection, timing of interventions and response to treatment failure. A number of different treatment paradigms have been suggested including stepwise treatment escalation, personalised disease management and an induction/consolidation approach, but as yet there remains no consensus as to the most efficacious and least deleterious overall route for this patient population.

Neuros have this debate all the time, Do something; Do nothing, offer the risk, be risk averse, offer something new, be a treatment ludite an god forbid......be innovative.....Is the way that NICE issues guidance on who can have what and when the answer, so as neuros don't have to think. Wonder how many neuros offer the choice above (no names please).

No doubt by reading blogs like this you are being proactive and are trying to understand the choices available, but there are many people that we are not reaching. They shy away from the reality and the knowledge. They rely on their neuros to make/offer the right choices.

What is the best way to engage with more people?

From some of the feedback I have heard it seemed that at the recent MS research day, organised by UCL, that the audience was populated by many MSer experts, who want more than a simple drugs pitch that they already know. Many want to know about stem cells, INSPIRE etc.

Tuesday, 24 June 2014

2014 Global MS Medical Summit, Budapest 2014 #MSBlog #MSResearch"For those attending the meeting in Budapest; as promised, my presentation from this morning. As usual you will notice that I have reused my slides. I hope I got the following messages across:

There is lots to be gained from preventing worsening of cognitive impairment in MS. #MSBlog #MSResearch

"The paper below is interesting. It is a mixed systemic review on definitions of cognitive impairment in MSers and a study testing these criteria. The bad news is that cognitive impairment occurs in early MS, which we already know. The good news is that the prevalence of cognitive impairment depends on how you define it. It is clear from this relatively small study (25 MSers with early MS and 52 MSers with late MS) that when cognitive impairment is found in early MS it is relatively mild. This is good news and implies that there is a lot to be gained by preventing further damage and to protect cognition from getting worse. This is why I refer to MS as being a preventable dementia."

BACKGROUND: Prevalence rates of cognitive impairment (CI) in MS vary between 40% and 80%. Differences in classification criteria for CI may explain this variance.

OBJECTIVE: This study reviewed and compared classification criteria for CI in patients with early and late MS.

METHODS: The paper consists of two parts: a systematic review of published classification criteria and the presentation of new data. Criteria were reviewed in respect to percentage of abnormal parameters and cut-offs concerning standard deviations. Thereafter, criteria were applied to cognitive data of 25 MSers with early MS (duration ≤ 2y), 52 matched MSers with late MS (≥12y), and 75 matched controls. The test battery assessed alertness, divided attention, mental flexibility, verbal and visual learning, memory, and visuospatial abilities.

RESULTS: Seventy classification criteria were revealed and grouped into 20 distinct approaches that can be subdivided into three basic classification strategies. Most commonly, CI was defined as performing 1.5 SD or 2 SD below the normative mean in 18-30% of test parameters (n=42). Other criteria utilized cognitive domains (n=6), composite indices (n=8), or combinations of cut-offs and strategies. The stringency of the criteria was correlated with the prevalence rate of CI (r=-.43) and disease duration (r=.48). In the new data, a substantial effect of classification criteria was found with a prevalence rate ranging from 0 to 68% in early and 4 to 81% in late MS. Increased rates of CI in patients vs. controls were found following 18 out of 20 criteria in the sample of late MS. In early MS, an increased rate of CI was only found following a liberal 1.5 SD cut-off criterion. Inter-rater reliability between all criteria was moderate. However, between criteria of comparable stringency the inter-rater reliability was found to be strong.

CONCLUSION: Classification based on different published criteria is not fully comparable and criteria need to be better homogenized.

BACKGROUND:Retinal optical coherence tomography (OCT) permits quantification of retinal layer atrophy relevant to assessment of neurodegeneration in multiple sclerosis (MS). Measurement artefacts may limit the use of OCT to MS research.OBJECTIVE:An expert task force convened with the aim to provide guidance on the use of validated quality control (QC) criteria for the use of OCT in MS research and clinical trials.METHODS:A prospective multi-centre (n = 13) study. Peripapillary ring scan QC rating of an OCT training set (n = 50) was followed by a test set (n = 50). Inter-rater agreement was calculated using kappa statistics. Results were discussed at a round table after the assessment had taken place.RESULTS:The inter-rater QC agreement was substantial (kappa = 0.7). Disagreement was found highest for judging signal strength (kappa = 0.40). Future steps to resolve these issues were discussed.CONCLUSION:Substantial agreement for QC assessment was achieved with aid of the OSCAR-IB criteria. The task force has developed a website for free online training and QC certification. The criteria may prove useful for future research and trials in MS using OCT as a secondary outcome measure in a multi-centre setting.

OCT is a technique for measuring retinal nerve loss. It may be a loose surrogate of what may be happening in the brain So a group of Optic Neuros got together to see how to do it. There was general agreement. You can read here about OSCAR-1B (click) or even go to the website

Background. Massage therapy is a noninvasive treatment that many individuals with multiple sclerosis (MS) use to supplement their conventional treatment.

Objective. We hypothesize that massage therapy will improve the leg function and overall quality of life (QoL) of MS patients. Design. A two-period (rest, massage) crossover design was used. Twenty-four individuals with MS ranging from 3.0 to 7.0 on the Expanded Disability Status Scale (EDSS) received Swedish massage treatments for four weeks. Exercise capacity and leg function as well as QoL were assessed using the Six-Minute Walk Test (6MWT) and the Quality of Life . Assessments were measured before and after a massage period and a rest period where no massages were employed.

Results. The results displayed no significant changes in 6MWT distances or QoL scores. However, the participants perceived improvement in overall health as expressed in written comments.

Conclusions. Massage is a safe, noninvasive treatment that may assist MS patients in managing the stress of their symptoms. Future studies with larger sample size and cortisol measures are warranted.

So nothing conclusive here I am afraid, you feel better after a massage.....em yep, many would have felt better if our Team had won in the World Cup but does that have anything to do with the actual disease process.

What has ageing go to do with MS? Progression maybe. #MSBlog #MSResearch

"In most studies age is the most powerful predictor of the onset of progressive MS. The older you are the more likely you are to have progressive disease. Children with MS almost never present with progressive MS and the time to onset of SPMS is longer. Why? Some in the field hypothesise that it is due to a failure of reparative mechanisms that are age-related. Some of you who have children will know how quickly they repair cuts compared to their aged-parents. There is good data in from animals supporting this hypothesis; aged rats remyelinate lesions a lot slower than young rats. The study below suggests the same happens in MS lesions. White matter in MS lesions in young MSers had better MTR metrics than lesions from older MSers. MTR is marker of remyelination. Lesions in young MSers were more likely to be remyelinated."

"What can we do about ageing? Ageing is a physiological process and therefore it may prove to be druggable in the future. You are all aware of the recent experiments of sewing together the circulations of young and older mice, which resulted in improvements in brain functioning of the older mice. These so called parabiosis experiments tell us that there is some soluble factor in young mice that promotes repair and augments brain function in older mice. If we can identify this factor, or cocktail of factors, we may be able to treat the ageing MS brain and promote repair. Is this another bit of science fiction? No I don't think. In addition to animal experiments we see clinical examples of delayed ageing and accelerated ageing. Therefore ageing is a physiological process and we will almost certainly be able to manipulate these processes. I predict that we will see anti-ageing medications in my lifetime and they may benefit MSers."

"For those of you interested in evolutionary medicine will know that evolution built in senescence, or ageing, into biological systems for a reason. If we remove or delay ageing we may affect natural selection and the delicate balance that exists between new and old. This is why any treatments that prevent or delay ageing will have ethical and philosophical ramifications."

BACKGROUND: MS is a heterogeneous disorder with a progressive course that is difficult to predict on a case-by-case basis. Natural history studies of MS have demonstrated that age influences clinical progression independent of disease duration.

OBJECTIVE: To determine whether age would be associated with greater CNS injury as detected by magnetization transfer MRI.

MATERIALS AND METHODS: 40 MSers were recruited from out-patient clinics into two groups stratified by age but with similar clinical disease duration as well as 13 controls age-matched to the older MS group. Images were segmented by automated programs and blinded readers into normal appearing white matter (NAWM), normal appearing gray matter (NAGM), and white matter lesions (WMLs) and gray matter lesions (GMLs) in the MS groups. WML and GML were delineated on T2-weighted 3D fluid-attenuated inversion recovery (FLAIR) and T1 weighted MRI volumes. Mean magnetization transfer ratio (MTR), region volume, as well as MTR histogram skew and kurtosis were calculated for each region.

RESULTS: All MTR measures in NAGM and MTR histogram metrics in NAWM differed between MS subjects and controls, as expected and previously reported by several studies, but not between MS groups. However, MTR measures in the WML did significantly differ between the MS groups, in spite of no significant differences in lesion counts and volumes.

Harnessing regulatory T (Treg) cells is a promising approach for treating autoimmune disease. However, inducing antigen-specific Treg cells that target inflammatory immune cells without compromising beneficial immune responses has remained an unmet challenge. We developed a pathway to generate autoantigen-specific Treg cells in vivo, which showed therapeutic effects on experimental autoimmune encephalomyelitis and nonobese diabetes in mice. Specifically, we induced apoptosis of immune cells by systemic sublethal irradiation or depleted B and CD8(+) T cells with specific antibodies and then administered autoantigenic peptides in mice with established autoimmune diseases. We demonstrated mechanistically that apoptotic cells triggered professional phagocytes to produce transforming growth factor-β, under which the autoantigenic peptides directed naïve CD4(+) T cells to differentiate into Foxp3(+) Treg cells instead of into T effector cells in vivo. These antigen-specific Treg cells specifically ameliorated autoimmunity without compromising immune responses to bacterial antigen. We have thus successfully generated antigen-specific Treg cells with therapeutic activity toward autoimmunity. The findings may lead to the development of antigen-specific Treg cell-mediated immunotherapy for multiple sclerosis and type 1 diabetes and also other autoimmune diseases.

Sunday, 22 June 2014

Do you have a swallowing problem? Another unrecognised problem that needs addressing. #ClinicSpeak #MSBlog #MSResearch"Our guest post on dysphagia and choking generated some interesting comments. Despite this being an issue most of you want to avoid thinking about, and discussing, it is a problem that affects a large number of MSers and has treatment and management implications."

"Dysphagia simply means discomfort or difficulties in swallowing. It can occur with solids and liquids and when severe can lead to aspiration, i.e. food goes down the trachea into the airways, or choking when it blocks the airway. Dysphagia usually occurs when MS is advance and associated with severe disability, but it can occur earlier in the disease as a result of a brain stem relapse. The brain stem is the part of the brain that controls swallowing. The study below from Brazil found dysphagia in 90% of the MSers they studied; this is a surprising result considering the average EDSS in this study was just below 4.0. Based on my own clinical experience 90% seems very high, unless I am missing dysphagia because I am not looking for it. Why it important to address this? Prevention. Dysphagia is the forerunner of aspiration pneumonia, a common cause of admission in MS and a common cause of death in advanced MS. As part of a holistic approach to MS we need to try and prevent aspiration pneumonia. I would therefore appreciate it if you could complete the following short survey; it includes a short dysphagia self-assessment."
Loading..."If after completing this survey you think you have a swallowing problem please discuss it with your neurologist or MS nurse. You may need a formal assessment to investigate the problem."Fernandes et al. Oropharyngeal dysphagia in patients with multiple sclerosis: do the disease classification scales reflect dysphagia severity? Braz J Otorhinolaryngol. 2013 Aug;79(4):460-5.

BACKGROUND: Multiple sclerosis is a neurological disease that involves swallowing disorders. Many studies have shown an association between neurological and swallowing performance, but results have been conflicting.

OBJECTIVE: To identify the frequency of dysphagia in MSers and neurological indicators that can represent the performance of swallowing.

RESULTS: Dysphagia was found in 90% of MSers. Among the clinical forms of the disease, the progressive forms (primary progressive and secondary progressive) were more frequently associated with severe dysphagia, while the relapsing-remitting form presented more often mild and moderate dysphagia. Regarding the Disability Scale for Functional Systems, cerebellar function, brainstem function and mental health were associated with dysphagia, especially in the severe form. Regarding the Extended Functional Disability Scale, higher scores were associated with severe dysphagia.

CONCLUSION: Dysphagia is common in MSers, especially in those with greater impairment of neurological functions.

Objective: Chronically demyelinated multiple sclerosis (MS) lesions are frequently characterized by scarce undifferentiated oligodendrocyte progenitor cells (OPCs) suggesting the exhaustion of a local OPC pool followed by failure of recruitment and differentiation. Stimulating prompt OPC recruitment following demyelination could improve myelin repair by providing sufficient numbers of remyelinating cells during the "repair-permissive" period. Understanding mechanisms that determine this process may have important therapeutic implications. We therefore investigated the role of the guidance molecule netrin-1 in OPC recruitment and CNS remyelination.

Methods: Netrin-1 expression was analysed immunohistochemically in different types of MS lesions and in the murine lysolecithin model of demyelination. The influence of netrin-1 on CNS remyelination was examined using gain and loss of function experiments.

Results: We show that in MS lesions, astrocytes upregulate netrin-1 expression early during demyelination and netrin-1 receptors are expressed by OPCs. In contrast, in the efficiently-repairing lysolecithin model of demyelination (astrocyte-free), netrin-1 expression is absent during early phases and detected concomitant with completion of OPC recruitment. In vitro migration assays demonstrated that netrin-1 is a chemorepellent for migrating adult OPCs. In mouse lesions, antibody-mediated disruption of netrin-1 function at the peak phase of recruitment increased OPC numbers. On the other hand, experimental induction of netrin-1 expression prior to OPC recruitment reduced the number of cells recruited and impaired remyelination. Interpretation: Our findings support the conclusion that netrin-1 expression within demyelinating MS plaques blocks OPC recruitment, which with repeated demyelinating episodes contributes to permanent remyelination failure.

Demyelination appears to result from both the failure of immature oligodendrocytes to develop into myelinating cells or that there are not enough myelinating cells in the area of demyelinating. This study suggests that netrin blocks the recruitment of myelinating cells. Netrins are a class of proteins involved in axon guidance. They are named after the Sanskrit word "netr", which means "one who guides."Netrins are chemotropic; a growing axon will either move towards or away from a higher concentration of netrin. Netrin attraction is mediated through UNC-40/DCC cell surface receptors and repulsion is mediated through UNC-5 receptors. Netrins also act as growth factors, encouraging cell growth activities in target cells. Therefore, if we can find effective netrin blockers this may be useful for repair

Saturday, 21 June 2014

Where is EBV acting in the causal pathway of MS? Early vs. Late? Central vs. Peripheral? #MSBlog #MSResearch

"The study below did not show any link between peripheral blood and viral titres to EBV and HHV-6 antigens and peripheral blood viral loads and disease course (relapses or disease progression). What can we conclude from this study? Does this mean that EBV and HHV-6 are unrelated to disease activity? The main problem with the anti-EBV serology is that they did not include antibodies to EBV nuclear antigen-1 or EBNA-1. The latter is the antigen that is responsible of keeping EBV in its latent state. Most of the studies showing a positive correlation between EBV and MS disease activity have been with this latent antigen. This study focused on antigens expressed when the virus is in its lytic phase; it may notbe lytic EBV infection that is driving the disease. With regard to viral loads the investigators have also only focused on the peripheral blood compartment. These viruses may be active in other compartments, for example the saliva and central nervous system (CNS). One confounder that has not been taken into account are DMTs. I can't find any reference in the paper to how many study subjects were on for example, interferon-beta. This is important; IFN-beta is an anti-viral and it may suppress viral activity in the peripheral compartment. Does this paper disprove the viral hypothesis? No! What it does say is that antibody titres to lytic antigens are not associated to MS disease activity and the peripheral blood is probably not the compartment to be looking at for viral activity."

BACKGROUND: Among the environmental factors associated with MS causation, some of the strongest associations are with EBV, and to a lesser extent human herpesvirus 6 (HHV6). Associations with clinical course are less conclusive, however.

METHODS: We evaluated serum anti-EBV-EA-R IgG and anti-HHV6 IgM, and EBV and HHV6 viral load (VL) for their associations with relapse, disability, and progression in disability in a prospective cohort of 198 participants with clinically definite MS.

RESULTS: Anti-EBV-EA-R IgG was detected in 81.8% of cases at study entry, and titres remained essentially unchanged during the study. Anti-HHV6 IgM was detected in only one participant, and EBV-VL (29%) and HHV6-VL (1.8%) were detected in a minority of samples, and where detected levels were low. Our previously demonstrated association between anti-HHV6 IgG and relapse hazard was not affected by adjustment for parameters of reactivation. We found no evidence that any of the viral markers were associated with disability or progression in disability. In relation to relapse, only EBV-VL was positively associated, although this was strongly influenced by a single individual.

CONCLUSION: Using a prospective cohort design, we found no convincing evidence that reactivation parameters of EBV or HHV6 were associated with subsequent MS relapse hazard or progression in disability, confirming previous findings, and indicating that herpes virus reactivation is not an important driver of relapse or disability in this established MS population.

BACKGROUND:Sexual dysfunction (SD) is a common reported problem in patients with multiple sclerosis (MS). AIMS:to examine frequency and distribution of SD dimensions and to determine whether SD is related to various clinical and demographic variables in female patients. MATERIALS AND METHODS:A total of 271 MS women (age: 19-50 years) participated in this cross-sectional study. We used a structured demographic and clinical interview and Multiple Sclerosis Intimacy and Sexuality Questionnaire-19 (MSISQ-19). Disability was rated by Expanded Disability Status Score (EDSS). RESULTS:63.5% (n = 173) of women had SD included 142 (52.4%) women with primary SD, 102 (37.5%) women with secondary SD and 120 (41%) women with tertiary SD. The most common SD-related complaint was orgasmic problem (41.2%). Women with primary SD were significantly older and had higher EDSS score. No significant relationship was found between primary SD and disease duration. Fatigue (OR = 2.69, 95% CI: 1.352-5.385, P = 0.005), memory and concentration complaints (OR = 1.915, 95% CI: 1.034-3.546, P = 0.039) and some of urinary symptoms such as frequency (OR = 2.108, 95% CI: 1.015-4.375, P = 0.045) were seem to be the significant predictors. Fatigue was also found to be the most powerful predicting factor for tertiary SD (OR = 2.793, 95% CI: 1.358-5.744 P = 0.005). CONCLUSION: SD, a common multifactorial problem among MS women, can arise at any time during the disease and with any level of disability. However, we found relationships between SD and some of clinical variables and symptoms. Understanding these relationships would help us to develop practical approach and treatment for SD.

I don't know how this got launched but it did. Remember Odds ratio (OR) of 2 equal twice as likely 0.5 is half as likely.

PML Risk Infographic

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